Tyrosine kinase receptors are trans-membrane proteins involved in signal transduction. They propagate growth factor signals from the cell surface to intracellular processes that control critical functions such as growth, differentiation, angiogenesis and inhibition of apoptosis. In malignancies, these signaling pathways are often exploited to optimize tumor growth and metastasis. One such family of receptor tyrosine kinases is the epidermal growth factor receptor (EGFR) tyrosine kinase. These receptors are overexpressed in a wide variety of major human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, esophageal, gynecological and thyroid cancers. Thus, an inhibitor of EGFR receptor tyrosine kinase is useful for treating a variety of human cancers.
Various pre-clinical and clinical studies have demonstrated that EGFR tyrosine kinase inhibitors can block cancer cell proliferation, metastasis and other EGFR-related signal transduction responses to achieve clinical anti-tumor therapeutic effects.
Erlotinib, an EGFR kinase inhibitor as disclosed in U.S. Pat. No. 5,747,498, was approved by US FDA for advanced non-small cell lung cancer and pancreatic cancer treatment in 2004, and has been clinically useful since. Subsequently, quinazoline-based EGFR kinase inhibitors have been extensively studied in search for new anti-cancer agents. Recent U.S. patents issued on quinazoline derivatives as potential therapeutic agents include U.S. Pat. Nos. 8,431,586; 8,426,430; 8,404,698; 8,399,667; and 8,349,856, just naming a few. These demonstrate that, due to the high demand of novel and better anticancer agents, new strategies and methods for discovering novel tyrosine kinase inhibitors as useful therapeutic agents are still being actively pursued.